Alzheimer's disease and spongiform encephalopathies are examples of conditions in which specific proteins transform from their native states into bundles of ordered fibrils termed amyloid. Protein concentration, point mutations, and solvent composition influence fibril formation, but a structural feature unique to amyloid-forming protein has not been detected.
Amyloid fibrils can be formed from different proteins. They are associated with neurodegenerative disorders such as Alzheimer's disease and the prion diseases (e.g., Creutzfeld-Jakob disease in humans, scrapie in sheep, and bovine spongiform encephalopathy), as well as other organ-specific and systemic amyloidoses (The Merck Manual, 16th ed., Merck Research Laboratories, Rahway, N.J., 1992, pp. 1052-1053; Kelly, 1996, Curr. Op. Struct. Biol. 6:11-17). The proteins involved in forming amyloid are constitutively present in a soluble state, but form insoluble aggregates under certain conditions (Chiti et al., 1999, Proc. Natl. Acad. Sci. USA 96:3590-3594). There are no obvious common properties in amino acid sequence, three dimensional structure, or function among the approximately 20 proteins that are known to be specifically associated with amyloid diseases (Sipe, 1992, Annu. Rev. Biochem. 61:947-975). In spite of the differences in native structures, the amyloid fibrils are similar, irrespective of the protein from which they originate (Dobson, 1999, TIBS 24:329-332). Amyloid fibrils are built up from a cross-β-scaffold, with β-strands perpendicular and β-sheets parallel to the fiber axis.
Amyloid diseases mostly occur without known precipitating factors (Lansbury, 1999, Proc. Natl. Acad. Sci. USA 96:3342-3344). Destabilizing point mutations can cause fibril formation of an otherwise stable protein, e.g., in lysozyme (Booth et al., 1997, Nature 385:787-793), but point mutations related to inherited forms of human prion diseases do not induce PrPSc (the disease-associated form of a prion) in vitro and are not generally destabilizing (Liemann et al., 1999, Biochemistry 38:3258-3267). The so-called Aβ (e.g., 142 residue) peptide associated with Alzheimer's disease is highly fibrillogenic, while peptides lacking residues 14-23 are not (Tjernberg et al., 1999, J. Biol. Chem. 274:12619-12625).